Down-regulation of Th1 responses in human neonates

Maródi, László

doi:10.1046/j.1365-2249.2002.01873.x

Cited by 62 publications

(42 citation statements)

References 27 publications

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“…There is a general consensus that newborn lymphocyte/adaptive responses are impaired or immature compared to those of adults (3). A relative reduction in Th1 responses (IFN-␥) with concomitant Th2 polarization in the newborn is often emphasized (1,2,26), although more recent studies also suggest an impairment in newborn lymphocyte-derived regulatory cytokines (such as IL-10) and regulatory T-cell function as well (14,36). We did find that IFN-␥ and IL-10 production was lower in newborn CBMC than in adult PBMC following HKGBS and PHA stimulation, consistent with previous data (19,45,46).…”

Section: Discussionmentioning

confidence: 99%

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

et al. 2011

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Group B streptococcus (GBS) is an important cause of early-and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBSinduced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.Streptococcus agalactiae (group B streptococcus [GBS]) is the leading infectious cause of death in the newborn (17), causing both early-and late-onset neonatal sepsis (EOS and LOS), characterized by septicemia, shock, and meningitis (16,18,31). The proportion of infants surviving extreme prematurity is increasing (11), and as a result preterm delivery is now the leading cause of neonatal morbidity and mortality. Preterm infants are exquisitely susceptible to both EOS and LOS; they suffer approximately a quarter of invasive GBS EOS cases and half of GBS LOS cases, with a Ͼ8-fold-greater mortality for EOS and 3-fold for LOS compared to term infants (29). While a proportion of the increased susceptibility to infection in preterm infants relates to the absence of passively acquired maternal IgG antibody, deficiencies in the early immune response to bacterial pathogens likely play a critical role (23). Several studies have addressed neonatal adaptive and humoral immune responses, such as complement activation and antibody production, but there has been little focus on innate immunity to bacterial pathogens and its relation to adaptive responses in this population (23,39).Innate immunity provides the first line of defense against bacterial infection and is therefore particularly important in the neonatal period (9). Additionally, the innate immune system, through activation of specif...

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Section: Discussionmentioning

confidence: 99%

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

et al. 2011

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“…Overall, a key finding of this study is that BPZE1 primes a persistent cell-mediated immune response against B. pertussis. The Th1/Th17 profile induced by BPZE1 may be important in the neonatal context, as Th1 responses typically are weak in human neonates (27,44) and during early life (10). In terms of pertussis immunity, priming this type of response can support long-lived memory and protection even when antibody responses have waned (24).…”

Section: Discussionmentioning

confidence: 99%

A Live, AttenuatedBordetella pertussisVaccine Provides Long-Term Protection against Virulent Challenge in a Murine Model

Skerry

Mahon

2011

Clin Vaccine Immunol

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“…Furthermore, the protective environment of the amniotic cavity of neonates and humanized mouse husbandry in a specificpathogen-free (SPF) facility induces a similar naive phenotype of the adaptive immune cells in neonates (15)(16)(17)(18) and humanized mice (11). The maturation of human T cells in the mouse thymus is dependent on the murine major histocompatibility complex (MHC) (lack of positive selection on human MHC).…”

Section: Il2rgmentioning

confidence: 99%

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

et al. 2013

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cBacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/ neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments.

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Down-regulation of Th1 responses in human neonates

Cited by 62 publications

References 27 publications

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

A Live, AttenuatedBordetella pertussisVaccine Provides Long-Term Protection against Virulent Challenge in a Murine Model

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

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